The penetrance of breast cancer in BRCA1 mutation carriers appears to vary considerably. The cumulative risk of breast cancer by age 70 for a BRCA1 mutation carrier has been estimated at anywhere from 44% to 80%. Variable penetrance and age of onset of breast cancer among related BRCA1 carriers sharing the same deleterious mutations has been observed and differences in breast cancer risk between population-based families and high-risk clinic-based families with the same mutations have also been detected. These and other observations strongly suggest the existence of common genetic variants that modify the risk of cancer in BRCA1 mutation carriers. Our goal in this study is to identify genetic modifiers of breast cancer risk in BRCA1 carriers through a genome wide association study with the intent of substantially improving understanding of the etiology of these tumors as well as pathologically related triple negative breast tumors. These modifiers should also prove useful for improved risk assessment of BRCA1 mutation carriers. We propose to accomplish this through a multi-stage approach using DNA samples from BRCA1 mutation carriers that have been collected through an international consortium. In stage 1 we aim to genotype 1,500 BRCA1 carriers with young onset breast cancer and 1,500 older unaffected BRCA1 carriers on 550,000 common variants and identify variants associated with risk of breast cancer. In stage 2 we will evaluate the 13,180 variants most significantly associated with breast cancer risk in 2,000 affected and 2,000 unaffected carriers and combine the data with stage 1 to increase statistical power. In stage 3 the 384 most significant variants will be further evaluated in 2,000 affected and 2,000 unaffected BRCA1 carriers and the data will be combined with data from stages 1 and 2. In parallel, because most BRCA1 mutant tumors are triple negative tumors, we will evaluate associations between the variants in stage 3 and risk of triple negative breast cancer using 1,500 basal breast cancer patients and 1,500 matching controls provided by the Breast Cancer Association Consortium. In stage 4 fine mapping of the genomic regions containing the most significantly associated variants will be conducted to identify the variants that likely account for the modification of breast cancer risk in BRCA1 carriers. PUBLIC HEALTH RELEVANCE: The identification of genetic modifiers of breast cancer risk in BRCA1 carriers will be useful for understanding the etiology of BRCA1 mutant breast cancer and triple negative breast cancer and for developing novel therapeutic targets. The modifiers may also lead to development of improved risk assessment models that better discriminate between high and lower risk BRCA1 mutation carriers.